Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The kinetics of prostaglandin-regulated cyclic AMP formation by intact human platelets were studied in the presence and absence of phosphodiesterase inhibitors. In the case of iloprost, a chemically stable analogue of prostaglandin I2, the shape of the time course varied with prostaglandin concentration. In the presence of phosphodiesterase inhibitors, low concentrations of iloprost gave a linear rate of cyclic AMP formation. At higher concentrations of iloprost, the initial rate increased as a saturable function of prostaglandin concentration but the curves decayed with time to give new linear rates of cyclic AMP formation with a different prostaglandin concentration dependence from the initial rates. Time courses were simulated using KINSIM [Anal. Biochem. 130: 134-145 (1983)], a kinetic simulation program that employs numerical integration, over a wide range of iloprost concentration (3 nM to 30 microM) by use of a simple model involving rapid activation of adenylate cyclase, followed by slow reversible transition of adenylate cyclase to an inactive form (desensitization) through a distinct inhibitory receptor. The model requires that the affinity for prostaglandins of both the stimulatory and inhibitory receptors declines with prostaglandin concentration, which may be related to the existence of high and low affinity receptor forms depending on the activation state of the appropriate GTP-binding protein. The same two-receptor model can be used to describe cyclic AMP metabolism in the absence of phosphodiesterase inhibitors, giving rise to characteristic peak and plateau effects in the time courses. The putative inhibitory receptor has an apparent affinity for prostaglandin lower than the stimulatory receptor in the case of iloprost and a higher affinity than the stimulatory receptor in the case of prostaglandin E1. The contribution of phosphodiesterase activation to the time course of cyclic AMP formation through phosphorylation by cyclic AMP-dependent protein kinase was assessed. It was shown that phosphodiesterase activation must be rapid. A plausible and perhaps complete description of prostaglandin-regulated cyclic AMP metabolism in platelets is presented.
 ...
PMID:Model of prostaglandin-regulated cyclic AMP metabolism in intact platelets: examination of time-dependent effects on adenylate cyclase and phosphodiesterase activities. 248 Dec 25

The shape of the time-course of cyclic AMP formation by intact human platelets in response to the stable prostaglandin I2 analogue iloprost varied with the concentration of the prostaglandin. At low concentrations of iloprost, the time-course showed a rise to a plateau with little subsequent decrease in cyclic AMP level. At high concentrations of iloprost, the initial rate of cyclic AMP formation was more rapid than at low concentrations, but the curves showed a marked time-dependent fall in cyclic AMP level to values below those observed at lower prostaglandin concentration. By contrast, PGE1 gave a rise and marked fall in cyclic AMP level at all concentrations of the prostaglandin and the curves did not cross. The time- and concentration-dependent fall in cyclic AMP level in response to iloprost was still apparent in the presence of phosphodiesterase inhibitors, indicating that inhibition of adenylate cyclase, rather than activation of cyclic AMP phosphodiesterases, was responsible for the fall in cyclic AMP level. Activators of protein kinase C, which phosphorylates platelet Ni and impairs its function, abolished the time-dependent fall in cyclic AMP level, indicating that Ni may be involved in prostaglandin-induced inhibition of adenylate cyclase. Time-courses were analyzed using an equation derived by Barber et al. (Adv. Cyc. Nuc. Res. 9, 507-516 (1978)) to yield rate constants for activation and inhibition of adenylate cyclase. Because of the difference in prostaglandin dependence of the activation and inhibition rate constants we propose that activation of adenylate cyclase in platelets is mediated by a rapid-acting stimulatory receptor, while time-dependent inhibition (desensitization) is mediated through a separate, slow-acting inhibitory receptor. The stimulatory receptor has an affinity for prostaglandin greater than the putative inhibitory receptor in the case of iloprost (as well as PGI2 and PGD2), and a lower affinity than the inhibitory receptor in the case of PGE1 (and PGE2). Prostaglandin-induced inhibition may be mediated through Ni.
 ...
PMID:Cyclic AMP turnover in response to prostaglandins in intact platelets: evidence for separate stimulatory and inhibitory prostaglandin receptors. 284 22